Novel process for preparation of optically pure and optionally substituted  2-(1-hydroxy-alkyl)-chromen-4-one  derivatives and their use in preparing pharmaceuticals

ABSTRACT

The present invention relates to compounds useful as pharmaceutical intermediates, to processes for preparing the intermediates, to intermediates used in the processes, and to the use of the intermediates in the preparation of pharmaceuticals. In particular, the present invention concerns enantiomerically pure optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one derivatives represented by formula (IA) and (IB), processes for preparing the alcohol derivatives and their use in preparing pharmaceuticals.

PRIORITY

This application claims the benefit of Indian Provisional PatentApplication No. 1737/CHE/2012 dated 4 May 2012 and U.S. ProvisionalPatent Application No. 61/671,956 dated 16 Jul. 2012; each of which ishereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to compounds useful as pharmaceuticalintermediates, to processes for preparing the intermediates, tointermediates used in the processes, and to the use of the intermediatesin the preparation of pharmaceuticals. In particular, the presentinvention concerns enantiomerically pure optionally substituted2-(1-hydroxy-alkyl)-chromen-4-one derivatives, processes for preparingthe alcohol derivatives and their use in preparing pharmaceuticals.

BACKGROUND OF THE INVENTION

International Publication No. WO 2011/055215, International PublicationNo. WO2012151525A1, U.S. Publication No. 2011/0118257, U.S. PublicationNo. 2012/0289496, Indian Provisional Patent Application Nos.1542/CHE/2011 dated 4 May 2011 and 81/CHE/2012 dated 9 Jan. 2012 (all ofwhich are incorporated herein by reference in their entirety for allpurposes) generally disclose 2,3 disubstituted-4H-chromen-4-onecompounds as PI3K inhibitors useful for the treatment, prevention and/oramelioration of kinase mediated diseases or disorders.

SUMMARY OF THE INVENTION

The present inventors have developed an improved process for preparingoptionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one derivatives(including 2-(1-hydroxy-alkyl), 6-substituted 4H-chromen-4-onecompounds), which may be used in the preparation of 2,3disubstituted-4H-chromen-4-one compounds. The process is particularlyuseful for preparing enantiomerically pure optionally substituted2-(1-hydroxy-alkyl)-chromen-4-one derivatives. The process isenantioselective and suitable for large scale production, has highyield, uses non-hazardous reagents and results in less waste.

The present invention provides processes for preparing a compound offormula (IA)

wherein

each occurrence of R is independently selected from hydrogen, hydroxy,halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenylalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heteroarylalkyl, —COOR^(x), —C(O)R^(x), —C(S)R^(x),—C(O)NR^(x)R^(y), —C(O)ONR^(x)R^(y), —NR^(x)R^(y), —NR^(x)CONR^(x)R^(y),—N(R^(x))SOR^(x), —N(R^(x))SO₂R, —(═N—N(R^(x))R^(y)), —NR^(x)C(O)OR^(y),—NR^(x)C(O)R^(y)—, —NR^(x)C(S)R^(y)—NR^(x)C(S)NR^(x)R^(y),—SONR^(x)R^(y), —SO₂NR^(x)R^(y), —OR^(x), —OR^(x)C(O)NR^(x)R^(y),—OR^(x)C(O)OR^(x), —OC(O)R^(x), —OC(O)NR^(x)R^(y),—R^(x)NR^(y)C(O)R^(Z), —R^(x)OR^(y), —R^(x)C(O)OR,—R^(x)C(O)NR^(x)R^(y), —R^(x)C(O)R^(y), —R^(x)OC(O)R^(y), —SR^(x),—SOR^(x), —SO₂R^(x), and —ONO₂, wherein each occurrence of R^(x), R^(y)and R^(z) is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted heteroaryl, substituted or unsubstitutedheteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedcycloalkenyl, substituted or unsubstituted heterocyclic ring,substituted or unsubstituted heterocyclylalkyl ring, or substituted orunsubstituted amino, or (i) any two of R^(x) and R^(y), when bound to acommon atom, are joined to form a substituted or unsubstituted,saturated or unsaturated 3-14 membered ring, which may optionallyinclude heteroatoms which may be the same or different and are selectedfrom O, NR^(z) or S, or (ii) any two of R^(x) and R^(y), when bound to acommon atom, are joined to form an oxo (═O), thio (═S) or imino(═NR^(f)) (wherein R^(f) is hydrogen or substituted or unsubstitutedalkyl);

R¹ is substituted or unsubstituted C₁₋₆ alkyl;

Cy¹ is a group (e.g., a monocyclic or bicyclic group) selected fromsubstituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclic group, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl; and

n is an integer selected from 0, 1, 2, 3 or 4.

In one embodiment, the compound is not selected from

or a salt thereof.

Further preferred is a compound of formula (IA) wherein R is alkyl(e.g., C₁-C₄ alkyl, such as methyl or ethyl) or halogen.

Further preferred is a compound of formula (IA) wherein R is chloro,fluoro or methyl.

Further preferred is a compound of formula (IA) wherein Cy¹ is amonocyclic group selected from substituted or unsubstituted aryl.

Further preferred is a compound of formula (IA) wherein Cy¹ is selectedfrom

Further preferred is a compound of formula (IA) wherein R¹ is methyl orethyl.

Further preferred is a compound of formula (IA) wherein n is 1.

In yet another embodiment is a compound selected from

-   1.    (R)-6-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one-   2. (R)-2-(1-hydroxyethyl)-5-methyl-3-phenyl-4H-chromen-4-one-   3. (R)-6-fluoro-2-(1-hydroxyethyl)-3-phenyl-4H-chromen-4-one-   4. (R)-2-(1-hydroxyethyl)-3-phenyl-4H-chromen-4-one-   5. (R)-3-(3-fluorophenyl)-2-(1-hydroxypropyl)-4H-chromen-4-one-   6. (R)-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one-   7. (S)-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one;

TABLE 1

Example-1

Example-2

Example-3

Example-4

Example-5

Example-6

Example-7

One embodiment is a process of preparing a compound of formula (IA)which includes

(a) treating a compound of formula (6) wherein R, n and Cy¹ are asdefined above with a compound of formula (A) wherein R¹ is as definedabove and Pg is a protecting group (such as benzyl)

and(b) deprotecting the compound formed in step (a) to obtain a compound offormula (IA), and optionally converting it to its salt.

In yet another embodiment, the reaction of compound of formula (6) withcompound of formula A is performed in presence of a suitable couplingreagent such as HATU((2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphospate), HBTU(O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate),TBTU (O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyl uroniumtetrafluoroborate), COMU (Morpholinium,4-[[[(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxayl](dimethylamino)methylene]-hexafluorophosphate), TOTU ((O-[(Ethoxycarbonyl)cyanomethylenamino]-N,N,N′,N′-tetra methyl uroniumtetrafluoroborate), HCTU((2-(6-Chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminiumhexafluorophosphate), TCTU(O-(6-Chloro-1-hydrocibenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumtetra fluoroborate), TATU(O-(7-Azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyl uronium tetrafluoroborate), TSTU (O—(N-Succinimidyl)-1,1,3,3-tetramethyl uraniumtetrafluoroborate), TDBTU (N,N,N′,N′-Tetramethyl-O-(3,4-dihydro-4-oxo-,2,3-benzotriazin-3-yl) uranium tetrafluoroborate), any other suitablecoupling reagents, or any combination of any of the foregoing.

Further preferred is where the reaction of compound of formula (6) withcompound of formula A is performed in presence of HATU, HBTU, TBTU orCOMU.

Further preferred is where the reaction of compound of formula (6) withcompound of formula A is performed in presence of HATU.

Another embodiment is a process for preparing a compound of formula (IB)

wherein all the variables are as defined above, the method includes thesteps of(a) treating a compound of formula (6), wherein R, n and Cy¹ are asdefined above, with a compound of formula (B) wherein R¹ is as definedabove and Pg is a protecting group (such as benzyl)

and(b) deprotecting the compound formed in step (a) to obtain a compound ofFormula (IB).

In one embodiment, the compound is not selected from

or a salt thereof.

Further preferred is a compound of formula (IB) wherein R is alkyl(e.g., C₁-C₄ alkyl, such as methyl or ethyl) or halogen.

Further preferred is a compound of formula (IB) wherein R is chloro,fluoro or methyl.

Further preferred is a compound of formula (IB) wherein Cy¹ is amonocyclic group selected from substituted or unsubstituted aryl.

Further preferred is a compound of formula (IB) wherein Cy¹ is selectedfrom

Further preferred is a compound of formula (IB) wherein R¹ is methyl orethyl.

Further preferred is a compound of formula (IB) wherein n is 1.

Yet another embodiment is a process for preparing a compound of formula(IA)

wherein all the variables are as defined above, the method includes thesteps of(a) converting a compound of formula (1)

wherein R and n are as defined above and Pg is a protecting group, to acompound of formula (2)

(b) converting the compound of formula (2) to a compound of formula (3)

(c) converting the compound of formula (3) to a compound of formula (5)

wherein R, n, Cy¹ and Pg are as described above;(d) deprotection of the compound of formula (5) to give a compound offormula (6)

(e) reacting the compound of formula (6) with a compound of formula (A)

to give a compound of formula (7a)

(f) deprotection of the compound of formula (7a) to give the desiredcompound of formula (IA); and(g) optionally, converting the compound of formula (IA) to a salt of thecompound.

The compound of Formula (1) may be converted to a compound of Formula(2) by treating the compound of formula (1) with hydroxyl amine or asalt thereof (such as NH₂OH.HCl) in presence of a base. The compound ofFormula (3) may be obtained by treating the compound of formula (2) withN,N′-carbonyldiimidazole (CDI). The compound of Formula (3) may beconverted to a compound of Formula (5) by treating the compound offormula (3) with a Grignard reagent of formula (4a)

Cy¹-CH₂—MgX

wherein X is halogen and Cy¹ is as defined above.

Yet another embodiment is a process for preparing a compound of formula(IB)

wherein all the variables are as defined above, the process includes thesteps of(a) converting a compound of formula (1)

to a compound of formula (2)

wherein R and n are as defined above and Pg is a protecting group (forexample by reacting the compound of formula (1) with hydroxylamine or asalt thereof (such as NH₂OH.HCl) in presence of a base);(b) converting the compound of formula (2) to a compound of formula (3)

(for example, by treating the compound of formula (2) withN,N′-carbonyldiimidazole (CDI));(c) converting the compound of formula (3) to a compound of formula (5)

wherein R, n, Cy¹ and Pg are as described above (for example by treatingthe compound of formula (3) with a Grignard reagent of formula (4a)

Cy¹-CH₂—MgX  4a

wherein X is halogen and Cy¹ is as defined above);(d) deprotection of the compound of formula (5) to give a compound offormula (6)

(e) reacting the compound of formula (6) with a compound of formula (B)

to give a compound of formula (7b)

(f) deprotection of the compound of formula (7b) to give the desiredcompound of formula (IB) wherein all the variables (R, R¹, n and Cy¹)are as described above in relation to Formula (IA); and(g) optionally, converting the compound of formula (IB) to a salt of thecompound.

In yet another embodiment, the reaction of compound of formula (6) withcompound of formula B is performed in presence of a suitable couplingreagent such as HATU((2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate), HBTU(O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate),TBTU (O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyl uroniumtetrafluoroborate), COMU (Morpholinium,4-[[[(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxayl](dimethylamino)methylene]-hexafluorophosphate), TOTU ((O-[(Ethoxycarbonyl)cyanomethylenamino]-N,N,N′,N′-tetra methyl uroniumtetrafluoroborate), HCTU((2-(6-Chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaniniumhexafluorophosphate), TCTU(O-(6-Chloro-1-hydrocibenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumtetra fluoroborate), TATU(O-(7-Azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyl uronium tetrafluoroborate), TSTU (O—(N-Succinimidyl)-1,1,3,3-tetramethyl uraniumtetrafluoroborate), TDBTU(N,N,N′,N′-Tetramethyl-O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)uranium tetrafluoroborate), any other suitable coupling reagents, or anycombination of any of the foregoing.

Further preferred is where the reaction of compound of formula (6) withcompound of formula B is performed in presence of HATU, HBTU, TBTU orCOMU.

Further preferred is where the reaction of compound of formula (6) withcompound of formula B is performed in presence of HATU.

Yet another embodiment is a process for inverting a compound of formula(IA) to yield a compound of formula (IB) comprising the step of

(a) reacting the compound of formula (IA) with R′—COOH (wherein R¹ isselected from substituted or unsubstituted alkyl or substituted orunsubstituted aryl) to provide a compound of formula IA-2

(b) treating the compound of formula (IA-2) with a suitable base in apolar solvent to yield a compound of formula (IB).

Yet another embodiment is a process for inverting a compound of formula(IB) to yield a compound of formula (IA) comprising the step of

(a) reacting the compound of formula (IB) with R′—COOH (wherein R¹ isselected from substituted or unsubstituted alkyl or substituted orunsubstituted aryl) to provide a compound of formula IB-2

(b) treating the compound of formula (IB-2) with a suitable base in apolar solvent to yield a compound of formula (IA).

Further preferred is where R′ is 4-chloro phenyl.

Further preferred is where the base is selected from inorganic bases,such as K₂CO₃, Na₂CO₃ or CsCO₃ and the polar solvent used is a suitablealcohol selected from methanol or ethanol.

Yet another embodiment is a process for preparing a compound of formula(IA-I)

wherein all the variables are as defined above, the method comprisingthe steps of(a) converting a compound of formula (1a)

to a compound of formula (2a)

wherein R and n are as defined above and Pg is a protecting group (forexample, reacting a compound of formula (1a) with hydroxylamine or asalt thereof (such as NH₂OH.HCl) in the presence of a base);(b) converting a compound of formula (2a) to a compound of formula (3a)

(for example, by treating the compound of formula (2a) withN,N′-carbonyldiimidazole (CDI));(c) converting a compound of formula (3a) to a compound of formula (5a)

(for example, by treating the compound of formula (3a) with a Grignardreagent of formula (4a)

Cy¹-CH₂—MgX  4a

wherein X is halogen and Cy¹ is as described above);(d) deprotection of the compound of formula (5a) to give a compound offormula (6a)

(e) reacting the compound of formula (6a) with a compound of formula (A)

to give a compound of formula (7aa)

(f) deprotection of the compound of formula (7aa) to give the desiredcompound of formula (IA-I) wherein all the variables (R, R¹, n and Cy¹)are as described above in relation to Formula (IA); and(g) optionally, converting the compound of formula (IA-I) to a salt ofthe compound.

Yet another embodiment is a process for preparing a compound of formula(IA-II)

wherein all the variables are as defined above, the methods comprisingthe step of(a) converting a compound of formula (1 b)

wherein R is as defined above and Pg is a protecting group, to acompound of formula (2b)

(for example, by treating a compound of formula (1a) with hydroxylamineor a salt thereof (such as NH₂OH.HCl) in the presence of a base);(b) converting a compound of formula (2b) to a compound of formula (3b)

(for example, by treating the compound of formula (2b) withN,N′-carbonyldiimidazole (CDI));(c) converting the compound of formula (3b) to a compound of formula(5b)

(for example, treating a compound of formula (3b) with a Grignardreagent of formula (4a)

Cy¹-CH₂—MgX 4a

wherein X is halogen and Cy¹ is as described above);(d) deprotection of the compound of formula (5b) to give a compound offormula (6b)

(e) reacting the compound of formula (6b) with a compound of formula (A)

to give a compound of formula (7ab)

and(f) deprotection of the compound of formula (7ab) to give the desiredcompound of formula (IA-II) wherein all the variables (R, R¹, n and Cy¹)are as described above in relation to Formula (IA); and(g) optionally, converting the compound of formula (IA-II) to a salt ofthe compound.

Yet another embodiment is a process for inverting a compound of formula(IA-I) to yield a compound of formula (IB-I) (shown below) comprisingthe step of

(a) reacting the compound of formula (IA-I) with R′—COOH (wherein R¹ isselected from substituted or unsubstituted alkyl or substituted orunsubstituted aryl) to provide a compound of formula (IA-I2)

(b) treating the compound of formula (IA-I2) with a suitable base in apolar solvent to yield a compound of formula (IB-I).

Yet another embodiment is a process for inverting a compound of formula(IB-I) to yield a compound of formula (IA-I) comprising the step of

(a) reacting the compound of formula (IB-I) with R¹—COOH (wherein R¹ isselected from substituted or unsubstituted alkyl or substituted orunsubstituted aryl) to provide a compound of formula (IB-I2)

(b) treating the compound of formula (IB-I2) with a suitable base in apolar solvent to yield a compound of formula (IA-I).

Yet another embodiment is a process for preparing a compound of formula(IB-I)

wherein all the variables are as defined above, the method comprisingthe steps of(a) reacting the compound of formula (6a) with a compound of formula (B)

to give a compound of formula (7ba)

(b) deprotection of the compound of formula (7ba) to give the desiredcompound of formula (IB-I) wherein all the variables (R, R¹, n and Cy¹)are as described above in relation to Formula (IA); and(c) optionally, converting the compound of formula (IB-I) to a salt ofthe compound.

Yet another embodiment is a process for preparing a compound of formula(IB-II)

wherein all the variables are as defined above, the method comprisingthe steps of(a) reacting the compound of formula (6b) with a compound of formula (B)

to give a compound of formula (7bb)

(b) deprotection of the compound of formula (7bb) to give the desiredcompound of formula (IB-II) wherein all the variables (R, R¹, n and Cy¹)are as described above in relation to Formula (IA); and(c) optionally, converting the compound of formula (IB-II) to a salt ofthe compound.

Yet another embodiment is a process for inverting a compound of formula(IA-II) to yield a compound of formula (IB-II) comprising the step of

(a) reacting the compound of formula (IA-II) with R¹—COOH (wherein R¹ isselected from substituted or unsubstituted alkyl or substituted orunsubstituted aryl) to provide a compound of formula IA-II2

(b) treating the compound of formula (IA-II2) with a suitable base in apolar solvent to yield a compound of formula (IB-II).

Yet another embodiment is a process for inverting a compound of formula(IB-II) to yield a compound of formula (IA-II) comprising the step of

(a) reacting the compound of formula (IB-II) with R¹—COOH (wherein R¹ isselected from substituted or unsubstituted alkyl or substituted orunsubstituted aryl) to provide a compound of formula IB-II2

(b) treating the compound of formula (IB-II2) with a suitable base in apolar solvent to yield a compound of formula (IA-II).

Yet another embodiment is a compound of formula (IA) or (IB)

or a salt thereof, wherein the variables R, n, Cy¹, and R¹ are definedas above.

In one embodiment, the compound of formula (IA) or (IB) has anenantiomeric excess (EE) of at least 75%, 90%, 95%, 97%, or 98%.

Yet another embodiment is the use of the compound of formula (IA), orany other intermediate described herein, for preparation of PI3Kinhibitors of formula (I)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof, wherein

the variables R, n, Cy¹, and R¹ are defined as above;

Cy² is selected from a substituted or unsubstituted heterocyclic group,substituted or unsubstituted aryl and substituted or unsubstitutedheteroaryl;

L₁ is absent or selected from —(CR^(a)R^(b))_(q)—, —O—, —S(═O)_(q)—,—NR^(a)— or —C(═Y)—;

each occurrence of R^(a) and R^(b) may be the same or different and areindependently selected from hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, —NR^(c)R^(d) (wherein R^(c)and R^(d) are independently hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, or (C₁₋₆)alkoxy) and —OR^(c)(wherein Re is substituted or unsubstituted (C₁₋₆)alkyl) or when R^(a)and R^(b) are directly bound to a common atom, they may be joined toform an oxo group (═O) or form a substituted or unsubstituted, saturatedor unsaturated 3-10 member ring (including the common atom to whichR^(a) and R^(b) are directly bound), which may optionally include one ormore heteroatoms which may be the same or different and are selectedfrom O, NR^(d) (wherein R^(d) is hydrogen or substituted orunsubstituted (C₁₋₆)alkyl) or S;

Y is selected from O, S, and NR^(a); and

q is 0, 1 or 2.

The compound of formula (I) may be prepared by

(a) treating the compound of formula (IA)

with Cy²-H (for example, by a Mitsunobu reaction) to give the desiredcompound of formula (I) or a tautomer thereof, N-oxide thereof,pharmaceutically acceptable ester thereof, prodrug thereof, orpharmaceutically acceptable salt thereof, wherein

R, R¹, n and Cy¹ are as described above in relation to Formula (IA).

Cy² is selected from a substituted or unsubstituted heterocyclic group,substituted or unsubstituted aryl and substituted or unsubstitutedheteroaryl; and

L₁ is absent; and

(b) optionally converting the compound of formula (I) to a salt of thecompound.

The compound of formula (I) may also be prepared by

(a) treating the compound of formula (IA)

with a phosphorus halide or mesyl chloride (or other mesyl halide) inthe presence of a base to give a compound of formula (8a)

wherein X¹ is halogen or —O-Mesyl (i.e., —O—SO₂CH₃); and(b) reacting the compound of formula (8a) with Cy²-H in the presence ofa base to give the desired compound of formula (I) or a tautomerthereof, N-oxide thereof, pharmaceutically acceptable ester thereof,prodrug thereof, wherein

R, R¹, n and Cy¹ are as described above in relation to Formula (IA);

Cy² is selected from a substituted or unsubstituted heterocyclic group,substituted or unsubstituted aryl and substituted or unsubstitutedheteroaryl; and

L₁ is absent; and

(c) optionally, converting the compound of formula (I) to a salt of thecompound.

Yet another embodiment provided is the use of the compound of formula(IA) for preparation of PI3K inhibitors of formula (II)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, wherein

R, R¹, n and Cy¹ are as described above in relation to Formula (IA);

Cy² is selected from a substituted or unsubstituted heterocyclic group,substituted or unsubstituted aryl and substituted or unsubstitutedheteroaryl; and

L₁ is NH.

The compound of formula (II) may be prepared by

(a) treating the compound of formula (IA)

with a phosphorus halide or mesyl chloride (or other mesyl halide) inthe presence of a base to give a compound of formula (8a)

wherein X¹ is halogen or —O-Mesyl;(b) converting the compound of formula (8a) to give a compound offormula (9a)

(for example, by treating the compound of formula (8a) with sodiumazide);(c) converting the compound of formula (9a) to give a compound offormula (10a)

(for example, by treating the compound of formula (8a) with triphenylphosphine);(d) coupling the compound of formula (10a) with a compound of formulaCy²-Lg, wherein Lg is a leaving group, in the presence of a base to givethe desired compound of formula (II); and(e) optionally, converting the compound of formula (II) to a salt of thecompound.

Yet another embodiment is the use of the compound of formula (IB), orany other intermediate described herein, for preparation of PI3Kinhibitors of formula (III)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof, wherein

the variables R, n, Cy¹, and R¹ are defined as above;

Cy² is selected from a substituted or unsubstituted heterocyclic group,substituted or unsubstituted aryl and substituted or unsubstitutedheteroaryl;

L₁ is absent or selected from —(CR^(a)R^(b))_(q)—, —O—, —S(═O)_(q)—,—NR¹— or —C(═Y)—;

-   -   each occurrence of R^(a) and R^(b) may be the same or different        and are independently selected from hydrogen, halogen, hydroxy,        cyano, substituted or unsubstituted (C₁₋₆)alkyl, —NR^(c)R^(d)        (wherein R^(c) and R^(d) are independently hydrogen, halogen,        hydroxy, cyano, substituted or unsubstituted (C₁₋₆)alkyl, or        (C₁₋₆)alkoxy) and —OR^(c) (wherein R^(c) is substituted or        unsubstituted (C₁₋₆)alkyl) or when R^(a) and R^(b) are directly        bound to a common atom, they may be joined to form an oxo group        (═O) or form a substituted or unsubstituted, saturated or        unsaturated 3-10 member ring (including the common atom to which        R^(a) and R^(b) are directly bound), which may optionally        include one or more heteroatoms which may be the same or        different and are selected from O, NR^(d) (wherein R^(d) is        hydrogen or substituted or unsubstituted (C₁₋₆)alkyl) or S;

Y is selected from O, S, and NR^(a); and

q is 0, 1 or 2.

The compound of formula (III) may be prepared by

(a) treating the compound of formula (IB)

with Cy²-H (for example, by a Mitsunobu reaction) to give the desiredcompound of formula (III) or a tautomer thereof, N-oxide thereof,pharmaceutically acceptable ester thereof, prodrug thereof, orpharmaceutically acceptable salt thereof, wherein

R, R¹, n and Cy¹ are as described above in relation to Formula (IB);

Cy² is selected from a substituted or unsubstituted heterocyclic group,substituted or unsubstituted aryl and substituted or unsubstitutedheteroaryl; and

L₁ is absent; and

(b) optionally converting the compound of formula (III) to a salt of thecompound.

The compound of formula (III) may also be prepared by

(a) treating the compound of formula (IB)

with a phosphorus halide or mesyl chloride (or other mesyl halide) inthe presence of a base to give a compound of formula (8b)

wherein X¹ is halogen or —O-Mesyl (i.e., —O—SO₂CH₃); and(b) reacting the compound of formula (8b) with Cy²-H in the presence ofa base to give the desired compound of formula (III) or a tautomerthereof, N-oxide thereof, pharmaceutically acceptable ester thereof,prodrug thereof, or pharmaceutically acceptable salt thereof, wherein

R, R¹, n and Cy¹ are as described above in relation to Formula (IB);

Cy² is selected from a substituted or unsubstituted heterocyclic group,substituted or unsubstituted aryl and substituted or unsubstitutedheteroaryl; and

L₁ is absent; and

(c) optionally, converting the compound of formula (III) to a salt ofthe compound.

Yet another embodiment provided is the use of the compound of formula(IB) for preparation of PI3K inhibitors of formula (IV)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof, wherein

R, R¹, n and Cy¹ are as described above in relation to Formula (IB);

Cy² is selected from a substituted or unsubstituted heterocyclic group,substituted or unsubstituted aryl and substituted or unsubstitutedheteroaryl; and

L₁ is NH.

The compound of formula (IV) may be prepared by

(a) treating the compound of formula (IB)

with a phosphorus halide or mesyl chloride (or other mesyl halide) inthe presence of a base to give a compound of formula (8b)

wherein X¹ is halogen or —O-Mesyl;(b) converting the compound of formula (8b) to give a compound offormula (9b)

(for example, by treating the compound of formula (8b) with sodiumazide);(c) converting the compound of formula (9b) to give a compound offormula (10b)

(for example, by treating the compound of formula (8b) with triphenylphosphine);(d) coupling the compound of formula (10b) with a compound of formulaCy²-Lg, wherein Lg is a leaving group, in the presence of a base to givethe desired compound of formula (IV); and(e) optionally, converting the compound of formula (IV) to a salt of thecompound.

In one preferred embodiment, the coupling reaction of the compound offormula 6 with the compound of formula A or B is performed in thepresence ofN-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU).

The protecting groups, such as those on the compounds of formulas 7a,7b, 7aa, 7ab, 7ba, and 7bb may be removed using suitable deprotectingagents, such as aluminium chloride, boron tribromide, or any combinationof the foregoing. Optionally the deprotection may be performed usingother suitable deprotecting agents including use of hydrogenation fordeprotection.

Yet another embodiment is a composition (e.g., a pharmaceuticalcomposition) comprising (a) a PI3K inhibitor of formula (I) or (II) or asalt thereof, and (b) a compound of formula (IA) or (IB) or a saltthereof. In one embodiment, the composition comprises at least about99.5% by weight of the PI3K inhibitor, and the compound of formula (IA)or (IB) in an amount up to 0.5% by weight, based upon the total ofcomponents (a) and (b). In another embodiment, the composition includesthe compound of formula (IA) or (IB) in an amount up to 0.2% or 0.1% byweight. The pharmaceutical composition can be, for example, a tablet orcapsule.

DETAIL DESCRIPTION OF THE INVENTION

As used herein the following definitions shall apply unless otherwiseindicated. Further many of the groups defined herein can be optionallysubstituted. The listing of substituents in the definition is exemplaryand is not to be construed to limit the substituents defined elsewherein the specification.

The term “alkyl” refers to a straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to eight carbon atoms, and which isattached to the rest of the molecule by a single bond, e.g., methyl,ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and1,1-dimethylethyl (t-butyl).

The term “alkenyl” refers to an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be a straight or branched orbranched chain having 2 to about 10 carbon atoms, e.g., ethenyl,1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl,1-butenyl, and 2-butenyl.

The term “alkynyl” refers to a straight or branched chain hydrocarbylradical having at least one carbon-carbon triple bond, and having in therange of 2 to up to 12 carbon atoms (with radicals having in the rangeof 2 to up to 10 carbon atoms presently being preferred) e.g., ethynyl,propynyl, and butnyl.

The term “alkoxy” denotes an alkyl, cycloalkyl, or cycloalkylalkyl groupas defined above attached via an oxygen linkage to the rest of themolecule. The term “substituted alkoxy” refers to an alkoxy group wherethe alkyl constituent is substituted (i.e., —O-(substituted alkyl)wherein the term “substituted alkyl” is the same as defined above for“alkyl”. For example, “alkoxy” refers to the group —O-alkyl, includingfrom 1 to 8 carbon atoms of a straight, branched, cyclic configurationand combinations thereof attached to the parent structure through aoxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy,cyclopropyloxy, and cyclohexyloxy.

The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ringsystem of 3 to about 12 carbon atoms such as cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groupsinclude perhydronaphthyl, adamantyl and norbornyl groups, bridged cyclicgroups, and sprirobicyclic groups, e.g., sprio (4,4) non-2-yl.

The term “cycloalkylalkyl” refers to a cyclic ring-containing radicalcontaining in the range of 3 up to about 8 carbon atoms directlyattached to an alkyl group which are then attached to the main structureat any carbon from the alkyl group that results in the creation of astable structure such as cyclopropylmethyl, cyclobutylethyl, andcyclopentylethyl.

The term “cycloalkenyl” refers to cyclic ring-containing radicalscontaining in the range of 3 up to about 8 carbon atoms with at leastone carbon-carbon double bond such as cyclopropenyl, cyclobutenyl, andcyclopentenyl. The term “cycloalkenylalkyl” refers to a cycloalkenylgroup directly attached to an alkyl group which are then attached to themain structure at any carbon from the alkyl group that results in thecreation of a stable structure.

The term “aryl” refers to aromatic radicals having in the range of 6 upto 20 carbon atoms such as phenyl, naphthyl, tetrahydronaphthyl,indanyl, and biphenyl.

The term “arylalkyl” refers to an aryl group as defined above directlybonded to an alkyl group as defined above, e.g., —CH₂C₆H₅ and —C₂H₅C₆H₅.

The term “heterocyclic ring” refers to a non-aromatic 3 to 15 memberring radical which consists of carbon atoms and at least one heteroatomselected from nitrogen, phosphorus, oxygen and sulfur. For purposes ofthis invention, the heterocyclic ring radical may be a mono-, bi-, tri-or tetracyclic ring system, which may include fused, bridged or spiroring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfuratoms in the heterocyclic ring radical may be optionally oxidized tovarious oxidation states. In addition, the nitrogen atom may beoptionally quaternized. The heterocyclic ring radical may be attached tothe main structure at any heteroatom or carbon atom that results in thecreation of a stable structure.

The term “heterocyclyl” refers to a heterocylic ring radical as definedabove. The heterocylcyl ring radical may be attached to the mainstructure at any heteroatom or carbon atom that results in the creationof a stable structure.

The term “heterocyclylalkyl” refers to a heterocylic ring radical asdefined above directly bonded to an alkyl group. The heterocyclylalkylradical may be attached to the main structure at carbon atom in thealkyl group that results in the creation of a stable structure. Examplesof such heterocycloalkyl radicals include, but are not limited to,dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl.

The term “heteroaryl” refers to an optionally substituted 5 to 14 memberaromatic ring having one or more heteroatoms selected from N, O, and Sas ring atoms. The heteroaryl may be a mono-, bi- or tricyclic ringsystem. Examples of such “heterocyclic ring” or “heteroaryl” radicalsinclude, but are not limited to, oxazolyl, thiazolyl, imidazolyl,pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl,indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl,isoquinolyl, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl,benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl,naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl,quinoxalinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl,piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl,2-oxoazepinyl, azepinyl, 4-piperidonyl, pyrrolidinyl, pyridazinyl,oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl,isoxazolidinyl, morpholinyl, thiazolinyl, thiazolidinyl, isothiazolyl,quinuclidinyl, isothiazolidinyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl,benzimidazolyl, thiadiazolyl, benzopyranyl, tetrahydrofuryl,tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl,oxadiazolyl, chromanyl, and isochromanyl. The heteroaryl ring radicalmay be attached to the main structure at any heteroatom or carbon atomthat results in the creation of a stable structure. The term“substituted heteroaryl” also includes ring systems substituted with oneor more oxide substituents, such as pyridinyl N-oxides.

The term “heteroarylalkyl” refers to a heteroaryl ring radical asdefined above directly bonded to an alkyl group. The heteroarylalkylradical may be attached to the main structure at any carbon atom fromalkyl group that results in the creation of a stable structure.

The term “cyclic ring” refers to a cyclic ring containing 3 to 10 carbonatoms.

The term “substituted” unless otherwise specified, refers tosubstitution with any one or any combination of the followingsubstituents which may be the same or different and are independentlyselected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo(═O), thio (═S), substituted or unsubstituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted aryl, substitutedor unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkenylalkyl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heteroarylalkyl, substituted or unsubstitutedheterocyclic ring, substituted heterocyclylalkyl ring, substituted orunsubstituted guanidine, —COOR^(x), —C(O)R^(x), —C(S)R^(x),—C(O)NR^(x)R^(y), —C(O)ONR^(x)R^(y), —NR^(x)CONR^(y)R^(z),—N(R^(x))SOR^(y), —N(R^(x))SO₂R^(y), —(═N—N(R)R^(y)), —NR^(x)C(O)OR^(y),—NR^(x)R^(y), —NR^(x)C(O)R^(y), —NR^(x)C(S)R^(y)—NR^(x)C(S)NR^(y)R^(z),—SONR^(x)R^(y)—, —SO₂NR^(x)R^(y), —OR^(x)—OR^(x)C(O)NR^(y)R^(z),—OR^(x)C(O)OR^(y)—, —OC(O)R^(x), —OC(O)NR^(x)R^(y),—R^(x)NR^(y)C(O)R^(z), —R^(x)OR^(y), —R^(x)C(O)OR^(y),—R^(x)C(O)NR^(y)R^(z), —R^(x)C(O)R^(x), —R^(x)OC(O)R^(y), —SR^(x),—SOR^(x), —SO₂R^(x), and —ONO₂, wherein R^(x), R^(y) and R^(z) in eachof the above groups can be hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substitutedor unsubstituted amino, substituted or unsubstituted heteroaryl,substituted or unsubstituted heteroarylalkyl, substituted orunsubstituted heterocyclic ring, or substituted heterocyclylalkyl ring,or any two of R^(x), R^(y) and R^(z) may be joined to form a substitutedor unsubstituted, saturated or unsaturated 3-10 membered ring, which mayoptionally include heteroatoms which may be the same or different andare selected from O, NR^(x) (e.g., R^(x) can be hydrogen or C₁₋₆ alkyl)or S. Substitution or the combinations of substituents envisioned bythis invention are preferably those that result in the formation of astable or chemically feasible compound. The term stable as used hereinrefers to the compounds or the structure that are not substantiallyaltered when subjected to conditions to allow for their production,detection and preferably their recovery, purification and incorporationinto a pharmaceutical composition. The substituents in theaforementioned “substituted” groups cannot be further substituted. Forexample, when the substituent on “substituted alkyl” is “substitutedaryl”, the substituent on “substituted aryl” cannot be “substitutedalkenyl”.

The term “halo”, “halide”, or, alternatively, “halogen” means fluoro,chloro, bromo or iodo. The terms “haloalkyl,” “haloalkenyl,”“haloalkynyl” and “haloalkoxy” include alkyl, alkenyl, alkynyl andalkoxy structures that are substituted with one or more halo groups. Forexample, the terms “fluoroalkyl” and “fluoroalkoxy” include haloalkyland haloalkoxy groups, respectively, in which the halo is fluorine.

The term “protecting group” or “Pg” refers to a substituent that isemployed to block or protect a particular functionality. Otherfunctional groups on the compound may remain reactive. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include, but are not limited to,acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl(CBz) and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, a“hydroxy-protecting group” refers to a substituent of a hydroxy groupthat blocks or protects the hydroxy functionality. Suitablehydroxy-protecting groups include, but are not limited to, acetyl andsilyl. A “carboxy-protecting group” refers to a substituent of thecarboxy group that blocks or protects the carboxy functionality.Suitable carboxy-protecting groups include, but are not limited to,—CH₂CH₂SO₂Ph, cyanoethyl, 2-(trimethylsilyl)ethyl,2-(trimethylsilyl)ethoxymethyl, -2-(p-toluenesulfonyl)ethyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, andnitroethyl. For a general description of protecting groups and theiruse, see T. W. Greene, Protective Groups in Organic Synthesis, JohnWiley & Sons, New York, 1991.

Certain of the compounds described herein contain one or more asymmetriccenters and can thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that can be defined, in terms of absolutestereochemistry, as (R)- or (S)-. The present chemical entities,pharmaceutical compositions and methods are meant to include all suchpossible isomers, including racemic mixtures, optically pure forms andintermediate mixtures. For instance, the non-limiting example ofintermediate mixtures include a mixture of isomers in a ratio of 10:90,13:87, 17:83, 20:80, or 22:78. Optically active (R)- and (S)-isomers canbe prepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers.

The term “tautomers” refers to compounds, which are characterized byrelatively easy interconversion of isomeric forms in equilibrium. Theseisomers are intended to be covered by this invention. “Tautomers” arestructurally distinct isomers that interconvert by tautomerization.“Tautomerization” is a form of isomerization and includes prototropic orproton-shift tautomerization, which is considered a subset of acid-basechemistry. “Prototropic tautomerization” or “proton-shifttautomerization” involves the migration of a proton accompanied bychanges in bond order, often the interchange of a single bond with anadjacent double bond. Where tautomerization is possible (e.g., insolution), a chemical equilibrium of tautomers can be reached. Anexample of tautomerization is keto-enol tautomerization. A specificexample of keto-enol tautomerization is the interconversion ofpentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Anotherexample of tautomerization is phenol-keto tautomerization. A specificexample of phenol-keto tautomerization is the interconversion ofpyridin-4-ol and pyridin-4(1H)-one tautomers.

A “leaving group or atom” is any group or atom that will, under thereaction conditions, cleave from the starting material, thus promotingreaction at a specified site. Suitable examples of such groups, unlessotherwise specified, are halogen atoms and mesyloxy,p-nitrobenzensulphonyloxy and tosyloxy groups.

The term “prodrug” refers to a compound, which is a precursor (forexample, an inactive precursor) of a compound, converted into its activeform in the body by normal metabolic processes. Prodrug design isdiscussed generally in Hardma, et al. (Eds.), Goodman and Gilman's ThePharmacological Basis of Therapeutics, 9th ed., pp. 11-16 (1996). Athorough discussion is provided in Higuchi, et al., Prodrugs as NovelDelivery Systems, Vol. 14, ASCD Symposium Series, and in Roche (ed.),Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press (1987). To illustrate, prodrugs can beconverted into a pharmacologically active form through hydrolysis of,for example, an ester or amide linkage, thereby introducing or exposinga functional group on the resultant product. The prodrugs can bedesigned to react with an endogenous compound to form a water-solubleconjugate that further enhances the pharmacological properties of thecompound, for example, increased circulatory half-life. Alternatively,prodrugs can be designed to undergo covalent modification on afunctional group with, for example, glucuronic acid, sulfate,glutathione, amino acids, or acetate. The resulting conjugate can beinactivated and excreted in the urine, or rendered more potent than theparent compound. High molecular weight conjugates also can be excretedinto the bile, subjected to enzymatic cleavage, and released back intothe circulation, thereby effectively increasing the biological half-lifeof the originally administered compound.

The term “ester” refers to a compound, which is formed by reactionbetween an acid and an alcohol with elimination of water. An ester canbe represented by the general formula RCOOR′.

These prodrugs and esters are intended to be covered within the scope ofthis invention.

Additionally the instant invention also includes the compounds whichdiffer only in the presence of one or more isotopically enriched atomsfor example replacement of hydrogen with deuterium or tritium, or thereplacement of a carbon by ¹³C- or ¹⁴C-enriched carbon.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of atoms that constitutesuch compounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds ofthe present invention, whether radioactive or not, are encompassedwithin the scope of the present invention.

Pharmaceutically acceptable salts forming part of this invention includesalts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu,Zn, and Mn; salts of organic bases such as N,N′-diacetylethylenediamine,glucamine, triethylamine, choline, hydroxide, dicyclohexylamine,metformin, benzylamine, trialkylamine, and thiamine; chiral bases suchas alkylphenylamine, glycinol, and phenyl glycinol; salts of naturalamino acids such as glycine, alanine, valine, leucine, isoleucine,norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, omithine, lysine, arginine, and serine; quaternaryammonium salts of the compounds of invention with alkyl halides, alkylsulphates such as MeI and (Me)₂SO₄; non-natural amino acids such asD-isomers or substituted amino acids; guanidine; and substitutedguanidine wherein the substituents are selected from nitro, amino,alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts andaluminum salts. Salts may include acid addition salts where appropriatewhich are sulphates, nitrates, phosphates, perchlorates, borates,hydrohalides, acetates, tartrates, maleates, citrates, fumarates,succinates, palmoates, methanesulphonates, benzoates, salicylates,benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.

Representative processes of the present invention include thosespecified below. The present invention should not be construed to belimited to them.

EXPERIMENTAL

The examples and preparations provided below further illustrate andexemplify the methods of preparing compounds of the invention. It is tobe understood that the scope of the present invention is not limited inany way by the scope of the following examples and preparations. In thefollowing examples molecules with a single chiral center, unlessotherwise noted, exist as a racemic mixture. Those molecules with two ormore chiral centers, unless otherwise noted, exist as a racemic mixtureof diastereomers. Single enantiomers/diastereomers may be obtained bymethods known to those skilled in the art.

Example 1(R)-6-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one

Step 1:(R)-2-(1-(benzyloxy)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

To 1-(5-fluoro-2-hydroxyphenyl)-2-(3-fluorophenyl) ethanone (11 g, 44.31mmol), in Dichloromethane (110 ml), HATU (33.7 g, 88.63 mmol) and(R)-Benzyloxypropionic acid (9.58 g, 53.17 mmol) were added and stirredfor ˜10 min. Triethylamine (67 ml, 478 mmol) was added dropwise andstirred at room temperature (RT) for 24 h. The reaction mixture wasquenched with water and extracted with Dichloromethane (2×250 ml). Theorganic layer was dried with sodium sulphate and concentrated undervacuum. The crude product was purified by column chromatography withethyl acetate:Petroleum ether to afford the title compound as aoff-white solid (10.9 g, 63%). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.85 (dd,J=8.1, 3.0 Hz, 1H), 7.58 (dd, J=9.1, 4.1 Hz, 1H), 7.47-7.39 (m, 1H),7.39-7.34 (m, 1H), 7.28-7.20 (m, 3H), 7.20-7.14 (m, 2H), 7.16-7.14 (m,1H), 6.99-7.89 (m, 2H), 4.50-4.31 (m, 3H), 1.56 (d, J=6.4 Hz, 3H). Mass:392.9 (M+).

Step 2:(R)-6-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one

To(R)-2-(1-(benzyloxy)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one(10.5 g, 26.69 mmol) in Dichloromethane (110 ml) cooled to 0° C.,anhydrous Aluminium chloride (5.35 g, 40.03 mmol) was added portion wiseand stirred for 1 h and then at RT for 2 h. The reaction mixture wasquenched with dilute aq. HCl (10 ml), extracted with Dichloromethane(2×50 ml). The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with ethyl acetate:petroleum ether to afford thetitle compound as off-white solid (6.5 g, 81%). ¹H-NMR (δ ppm, CDCl₃,400 MHz): 7.86 (dd, J=8.3, 3.0 Hz, 1H), 7.56 (dd, J=9.2, 4.2 Hz, 1H),7.45 (m, 2H), 7.12-6.99 (m, 3H), 4.76 (q, J=6.6 Hz, 1H), 1.55 (d, J=6.6Hz, 3H). Mass: 303.2 (M⁺+1). Purity: 99.78%. [α]²⁵ _(D) 0.287 (c=1,CHCl₃). Enantiomeric excess: 97.74%, enriched in the late eluting isomer(retention time: 10.93 min.) as determined by HPLC on a chiralpak AD-Hcolumn.

Example 2 (R)-2-(1-hydroxyethyl)-5-methyl-3-phenyl-4H-chromen-4-one

Step 1: (R)-2-(1-(benzyloxy)ethyl)-5-methyl-3-phenyl-4H-chromen-4-one

To 1-(2-hydroxy-6-methylphenyl)-2-phenylethanone (0.400 g, 1.76 mmol) indichloromethane (4 ml), R(+)-benzyloxypropionic acid (0.382 g, 2.12mmol) and HATU (2.01 g, 5.30 mmol) were added followed by triethylamine(2.6 ml, 19.08 mmol). After 20 h at room temperature, the reactionmixture was quenched with water, extracted with ethyl acetate, driedover sodium sulphate and concentrated. The crude product was columnchromatographed with ethyl acetate:petroleum ether to afford the titlecompound as off-white solid (0.080 g, 12%). ¹H-NMR (δ ppm, CDCl₃, 400MHz): 7.55 (t, J=8.1 Hz, 1H), 7.43-7.13 (m, 12H), 4.47 (m, 2H), 4.30 (d,J=11.8 Hz, 1H), 2.84 (s, 3H), 1.54 (d, J=6.5 Hz, 3H). Mass: 370.9 (M).

Step 2: (R)-2-(1-hydroxyethyl)-5-methyl-3-phenyl-4H-chromen-4-one

To (R)-2-(1-(benzyloxy)ethyl)-5-methyl-3-phenyl-4H-chromen-4-one (0.850g, 2.29 mmol) in dichloromethane (8.0 ml) at −78° C., boron tribromide(0.78 ml, 1M in dichloromethane, 4.58 mmol) was added slowly andmaintained for 4 h. The reaction mass was quenched at −78° C. using 2NHCl (50 ml), extracted with ethyl acetate, dried over sodium sulphateand concentrated. The crude product was column chromatographed withethyl acetate:petroleum ether to afford the title compound aspale-yellow liquid (0.200 g, 31%). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.54(t, J=8.0 Hz, 1H), 7.46-7.26 (m, 6H), 7.13 (d, J=7.4 Hz, 1H), 4.71 (q,J=6.6 Hz, 1H), 2.83 (s, 3H), 1.53 (d, J=6.6 Hz, 3H). Mass: 280.8 (M⁺).

Example 3 (R)-6-fluoro-2-(1-hydroxyethyl)-3-phenyl-4H-chromen-4-one

Step 1: (R)-2-(1-(benzyloxy)ethyl)-6-fluoro-3-phenyl-4H-chromen-4-one

To 1-(5-fluoro-2-hydroxyphenyl)-2-phenylethanone (2.00 g, 8.68 mmol), indichloromethane (15 ml), HATU (6.60 g, 17.36 mmol), andR-(+)2-benzyloxypropionic acid (1.87 g, 10.42 mmol) were added andstirred for 10 min. Triethylamine (13.0 ml, 93.7 mmol) was addeddropwise and stirred at RT for 24 h. The reaction mixture was quenchedwith water, extracted with dichloromethane, dried over sodium sulphateand concentrated under reduced pressure. The crude product was purifiedby column chromatography with ethyl acetate:petroleum ether to affordthe title compound as a yellow solid (0.634 g, 19%). ¹H-NMR (δ ppm,CDCl₃, 400 MHz): 7.87 (dd, J=8.2, 3.1 Hz, 1H), 7.59 (dd, J=9.1, 4.1 Hz,1H), 7.45-7.37 (m, 4H), 7.25-7.15 (m, 7H), 4.53 (q, J=6.5 Hz, 1H), 4.43(d, J=11.8 Hz, 1H), 4.33 (d, J=11.7 Hz, 1H), 1.56 (d, J=6.5 Hz, 3H).Mass: 375.0 (M⁺).

Step 2: (R)-6-fluoro-2-(1-hydroxyethyl)-3-phenyl-4H-chromen-4-one

To (R)-2-(1-(benzyloxy)ethyl)-6-fluoro-3-phenyl-4H-chromen-4-one (0.63g, 1.68 mmol) in dichloromethane (6 ml) cooled to 0° C., aluminiumchloride (0.330 g, 2.52 mmol) was added portion wise and stirred at RTfor 6 h. The reaction mixture was quenched with 2N HCl solution,extracted with dichloromethane, dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with ethyl acetate:petroleum ether to afford thetitle compound as yellow solid (0.348 g, 73%). ¹H-NMR (δ ppm, CDCl₃, 400MHz): 7.83 (m, 1H), 7.76 (m, 2H), 7.46 (m, 3H), 7.30 (m, 2H), 5.60 (d,J=4.9 Hz, 1H), 4.53 (m, 1H), 1.38 (d, J=6.5 Hz, 3H). Mass: 285.2 (M++1).Purity: 86.82%. [α]²⁵ _(D) −1.18 (c=1, CHCl₃). Enantiomeric excess:97.8%, enriched in the late eluting isomer (retention time: 11.39 min.)as determined by HPLC on a chiralpak AD-H column.

Example 4 (R)-2-(1-hydroxyethyl)-3-phenyl-4H-chromen-4-one

Step 1: (R)-2-(1-(benzyloxy)ethyl)-3-phenyl-4H-chromen-4-one

The title compound was obtained as a yellow solid (1.50 g, 37%) byfollowing the procedure described for Step 1 of Example 3 from1-(2-hydroxyphenyl)-2-phenylethanone (2.40 g, 11.30 mmol),dichloromethane (30 ml), HATU (8.60 g, 22.60 mmol),R-(+)2-benzyloxypropionic acid (2.44 g, 13.56 mmol) and triethylamine(17.0 ml, 122.11 mmol) which was used as such in next step.

Step 2: (R)-2-(1-hydroxyethyl)-3-phenyl-4H-chromen-4-one

The title compound was obtained as a yellow solid (0.650 g, 58%) byfollowing the procedure described for Step 2 of Example 3 from(R)-2-(1-(benzyloxy)ethyl)-3-phenyl-4H-chromen-4-one (1.50 g, 4.20 mmol)in dichloromethane (15 ml) cooled to 0° C. and aluminium chloride (0.843g, 6.30 mmol) ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.24 (dd, J=7.9, 1.5 Hz,1H), 7.72 (m, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.46-7.37 (m, 4H), 7.29 (m,2H), 4.79 (q, J=6.6 Hz, 1H), 1.55 (d, J=6.6 Hz, 3H). Mass: 267.0 (M).Purity: 98.28%. [α]²⁵ _(D) 6.53 (c=1, CHCl₃). Enantiomeric excess:92.2%, enriched in the late eluting isomer (retention time: 10.38 min.)as determined by HPLC on a chiralpak AD-H column.

Example 5 (R)-3-(3-fluorophenyl)-2-(1-hydroxypropyl)-4H-chromen-4-one

Step 1: (R)-2-(1-(benzyloxy)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The title compound was obtained as a yellow solid (1.65 g, 45%) byfollowing the procedure described for Step 1 of Example 3 from2-(3-fluorophenyl)-1-(2-hydroxyphenyl)ethanone (2.15 g, 9.36 mmol),dichloromethane (20 ml), HATU (4.27 g, 11.23 mmol),R-(+)2-benzyloxybutyric acid (2.00 g, 10.29 mmol) and triethylamine(14.0 ml, 101.1 mmol). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.24 (dd, J=7.9,1.5 Hz, 1H), 7.74 (dt, J=7.1, 1.7 Hz, 1H), 7.58 (dd, J=8.3, 0.4 Hz, 1H),7.44-7.06 (m, 10H), 4.51 (d, J=7.8 Hz, 1H), 4.34 (d, J=7.8 Hz, 1H), 4.25(dd, J=7.8, 6.2 Hz, 1H), 2.17-1.90 (m, 2H), 0.95 (t, J=7.5 Hz, 3H).Mass: 389.0 (M+).

Step 2: (R)-3-(3-fluorophenyl)-2-(1-hydroxypropyl)-4H-chromen-4-one

The title compound was obtained as a yellow solid (0.552 g, 48%) byfollowing the procedure described for Step 2 of Example 3 from(R)-2-(1-(benzyloxy)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one (1.50 g,3.86 mmol) in dichloromethane (15 ml) cooled to 0° C. and aluminiumchloride (1.00 g, 7.72 mmol). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.24 (dd,J=8.0, 1.6 Hz, 1H), 7.72 (m, 1H), 7.52 (dd, J=8.4, 0.5 Hz, 1H), 7.44 (m,2H), 7.12-7.01 (m, 3H), 4.49 (t, J=7.0 Hz, 1H), 1.94 (m, 2H), 0.93 (t,J=7.5 Hz, 3H). Mass: (299.0 (M⁺). Purity: 96.93%. [α]²⁵ _(D) −14.73(c=1, CHCl₃). Enantiomeric excess: 85.92%, enriched in the fast elutingisomer (retention time: 8.57 min.) as determined by HPLC on a chiralpakAS-3R column.

Example 6 (R)-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one

Step-1: (R)-2-(1-(benzyloxy)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To 2-(3-fluorophenyl)-1-(2-hydroxyphenyl)ethanone (10.0 g, 43.43 mmol)in dichloromethane (75 ml), HATU (33.0 g, 86.86 mmol) andR-(+)2-benzyloxypropionic acid (9.39 g, 52.12 mmol) were added andstirred for 10 min. Triethylamine (65.4 ml, 0.469 mol) was addeddropwise and stirred at RT for 24 h. The reaction mixture was quenchedwith water, extracted with dichloromethane, dried over sodium sulphateand concentrated under reduced pressure. The crude product was purifiedby column chromatography with ethyl acetate:petroleum ether to affordthe title compound as a off-white solid (9.0 g, 55%). ¹H-NMR (δ ppm,CDCl₃, 400 MHz): 8.23 (dd, J=7.9, 1.2 Hz, 1H), 7.74-7.70 (m, 1H), 7.58(d, J=8.3 Hz, 1H), 7.43 (t, J=7.2 Hz, 1H), 7.37 (q, J=7.2 Hz, 1H),7.29-7.15 (m, 5H), 7.09 (dt, J=8.6, 1.7 Hz, 1H), 7.00-6.90 (m, 2H),4.51-4.35 (m, 3H), 1.57 (d, J=6.4 Hz, 3H).

Step 2: (R)-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one

To (R)-2-(1-(benzyloxy)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one (5.0g, 13.35 mmol) in dichloromethane (50 ml) cooled to −78° C., borontribromide (1M in dichloromethane, 36.5 ml, 0.145 mmol) was addeddropwise and stirred for 1 h. The reaction mixture was quenched with 2NHCl solution, extracted with dichloromethane, dried over sodium sulphateand concentrated under reduced pressure. The crude product was purifiedby column chromatography with ethyl acetate:petroleum ether to afford(R)-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one as anoff-white solid (3.05 g, 80%). ¹H-NMR (6 ppm, CDCl₃, 400 MHz): 8.24 (dd,J=7.9, 1.5 Hz, 1H), 7.73 (m, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.44 (m, 2H),7.13-7.01 (m, 3H), 4.71 (q, J=6.6 Hz, 1H), 1.56 (d, J=6.5 Hz, 3H). Mass:284.9 (M⁺). Purity: 99.73%. [α]²⁵ _(D) −0.605 (c=1, CHCl₃). Enantiomericexcess: 95.2%, enriched in the late eluting isomer (retention time:10.19 min.) as determined by HPLC on a chiralpak AD-H column.

Example 7

Step-1: (S)-1-(3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl4-chlorobenzoate

To a solution of Example 6 (2.00 g, 7.03 mmol) in THF (20 ml),4-chlorobenzoic acid (1.10 g, 2.15 mmol) and triphenylphosphine (2.70 g,10.55 mmol) were added and heated to 45° C. followed by anddiisopropylazodicarboxylate (2.0 ml, 10.55 mmol). The mixture wasrefluxed for 1 h, concentrated and the residue was purified by columnchromatography with ethyl acetate:petroleum ether to afford the titlecompound as off-white solid (2.35 g, 79%) which was used withoutpurification in the next step.

Step-2: (S)-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one

To (R)-11-(3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl4-chlorobenzoate (2.35 g, 5.55 mmol) in methanol (20 ml), potassiumcarbonate (0.384 g, 2.77 mmol) was added at 0° C. After 30 min. themethanol was concentrated, quenched with 2N HCl and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with ethyl acetate:petroleum ether toafford(S)-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one as paleyellow solid (1.15 g, 73%). Enantiomeric excess: 95.2%, enriched in thefast eluting isomer (retention time: 8.75 min.) as determined by HPLC ona chiralpak AD-H column.

In order to fully understand and demonstrate the various embodiment ofthe invention, provided herein below are certain examples in detail asan illustration to enable the utility and/or performance of the presentinvention.

Illustration 1(R)-2-(1-(4-amino-3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

This example is also described in Example 59 of WO 2012/151525. To asolution of3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine(0.080 g, 0.254 mmol) in THF (2 ml), tris(4-methoxyphenyl)phosphine(0.134 g, 0.381 mmol) and diisopropylazodicarboxylate (0.07 ml, 0.381mmol) is added and stirred at room temperature (RT) for 10 minutes. Tothis mixture(−)-5-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one(0.077 g, 0.254 mmol) is added and stirred for 12 h. The reactionmixture is diluted with water and extracted with ethyl acetate. Theorganic layer is dried over sodium sulphate and concentrated underreduced pressure. The crude product is purified by column chromatographywith methanol:dichloromethane to afford the title compound as anoff-white solid. MP: 242-245° C. Enantiomeric excess: 96.21% Mass: 599.1(M⁺+1).

Illustration 2(+)-2-(1-(9H-purin-6-ylamino)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

This example is also described in Example 68 of WO 2012/151525. Thetitle compound is obtained as an off-white solid using a procedure thatis similar to the one described for illustration 1 from tert-butyl9-trityl-9H-purin-6-ylcarbamate (0.235 g, 0.494 mmol),(−)-5-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one(0.150 g, 0.494 mmol), triphenylphosphine (0.194 g, 0.741 mmol), THF (8ml) and diisopropylazodicarboxylate (0.15 ml, 0.749 mmol), followed bythe cleavage of the intermediate with trifluoroacetic acid (1.8 ml) anddichloromethane (5 ml). MP: 194-197° C. Enantiomeric excess: 99.62%.[α]²⁵ _(D) 142.00 (c=1, CHCl₃). Mass: 420.1 (M⁺+1).

Illustration 3 (+)2-(1-(4-amino-3-(4-isopropoxy-3-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

This example is also described in Example 114 of WO 2012/151525. Thetitle compound is obtained as off-white solid using a procedure that issimilar to the one described for Illustration 1 from3-(4-isopropoxy-3-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine(0.150 g, 0.529 mmol),(−)-5-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one(0.145 g, 0.481 mmol), tris-4-methoxytriphenylphosphine (0.254 g, 0.721mmol), THF (3 ml) and diisopropylazodicarboxylate (0.14 ml, 0.721 mmol).MP: 217-220° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.22 (s, 1H), 7.61(dt, J=8.4, 5.4 Hz, 1H), 7.43 (m, 2H), 7.29 (m, 2H), 7.05-6.97 (m, 4H),6.92 (d, J=9.4 Hz, 1H), 6.07 (q, J=7.1 Hz, 1H), 5.42 (s, 2H), 4.63(quintet, J=6.0 Hz, 1H), 2.28 (s, 3H), 1.97 (d, J=7.1 Hz, 3H), 1.39 (d,J=6.0 Hz, 6H). Enantiomeric excess: 100% as determined by HPLC on achiralpak AD-H column, enriched in the fast eluting isomer (retentiontime=9.36 min) [α]²⁵ _(D) 176.04 (c=1, CHCl₃).

Illustration 4 (−)2-(1-(4-amino-3-(4-isopropoxy-3-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

This example is also described in Example 115 of WO 2012/151525. Thetitle compound is obtained as an off-white solid using a procedure thatis similar to the one described for Illustration 1 from3-(4-isopropoxy-3-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine(0.128 g, 0.453 mmol),(+)-5-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one(0.125 g, 0.412 mmol), tris-4-methoxytriphenylphosphine (0.217 g, 0.618mmol), THF (3 ml) and diisopropylazodicarboxylate (0.12 ml, 0.618 mmol).MP: 221-224° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.22 (s, 1H), 7.61(dt, J=8.4, 5.5 Hz, 1H), 7.43 (m, 2H), 7.29 (m, 2H), 7.05-6.95 (m, 4H),6.92 (d, J=9.5 Hz, 1H), 6.05 (q, J=7.1 Hz, 1H), 5.40 (s, 2H), 4.62(quintet, J=6.0 Hz, 1H), 2.28 (s, 3H), 1.99 (d, J=7.2 Hz, 3H), 1.39 (d,J=6.0 Hz, 6H). Enantiomeric excess: 99.6% as determined by HPLC on achiralpak AD-H column, enriched in the late eluting isomer (retentiontime=11.43 min) [α]²⁵ _(D) −183.59 (c=1, CHCl₃).

Illustration 5(S)/(R)-2-(1-aminoethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

This example is also described in Intermediate 141-143 of WO2012/151525.

Step-1:(S)/(R)-1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethylmethanesulfonate

To a cooled solution of(+)-5-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one(0.800 g, 2.63 mmol) in dichloromethane (16 ml) and triethylamine (1.10ml, 7.91 mmol), methanesulphonyl chloride (0.400 ml, 5.27 mmol) is addedstirred at room temperature for 2 h. The reaction mass is quenched withwater, extracted with dichloromethane, dried over sodium sulphate andconcentrated to afford the title compound as brown solid which is usedas such in next step.

Step-2:(S)/(R)-2-(1-azidoethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of(S)/(R)-1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethylmethane sulfonate (0.900 g, 2.36 mmol) in DMF (18 ml), sodium azide(0.306 g, 4.72 mmol) is added and heated to 60° C. After 2 h, thereaction mass is quenched with water, extracted with dichloromethane,dried over sodium sulphate and concentrated. The crude product is columnchromatographed with ethyl acetate:petroleum ether to afford the titlecompound as a brown liquid which is used as such in next step.

Step-3:(S)/(R)-2-(1-aminoethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of(S)/(R)-2-(1-azidoethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one(0.600 g, 1.82 mmol) in THF (2.4 ml) and water (1.2 ml),triphenylphosphine (0.455 g, 1.73 mmol) is added and stirred at roomtemperature for 14 h. The reaction mass is quenched with water,extracted with ethyl acetate, dried over sodium sulphate andconcentrated. The crude product is column chromatographed withmethanol:dichloromethane to afford the title compound as a brown liquid.

Illustration 6(S)/(R)-5-fluoro-2-(1-(2-fluoro-9H-purin-6-ylamino)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

This example is also described in Example 136 of WO 2012/151525. To asolution of(S)/(R)-2-(1-aminoethyl)-5-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one(0.22 g, 0.730 mmol), tert-butanol (1.5 ml) N,N-diisopropylethylamine(0.25 ml, 1.46 mmol) and 6-chloro-2-fluoro-9H-purine (0.102 g, 0.663mmol) are added and heated to reflux for 248 h. The reaction mixture isconcentrated, quenched with water, extracted with ethyl acetate, driedwith sodium sulphate and concentrated. The crude product is purified bycolumn chromatography with methanol:ethyl acetate to afford the titlecompound as a brown solid. MP: 183-186° C. Mass: 437.9 (M⁺).Enantiomeric excess: 33% as determined by HPLC on a chiralpak AD-Hcolumn, enriched in the fast eluting isomer (retention time=7.21 min).

Illustration 7(S)-2-(1-(9H-purin-6-ylamino)ethyl)-6-bromo-3-phenyl-4H-chromen-4-one

This example is also described in Example 24 of WO 2011/055215. To asolution of (S)-2-(1-aminoethyl)-6-bromo-3-phenyl-4H-chromen-4-one (0.20g, 0.581 mmoles) in tert-butanol (6 ml), N,N-diisopropylethyl amine (0.2ml, 1.162 mmoles) and 6-bromopurine (0.087 g, 0.435 mmoles) are addedand refluxed for 24 h. The reaction mixture is concentrated, dilutedwith water, extracted with ethyl acetate. The organic layer is driedover sodium sulphate and concentrated under reduced pressure. The crudeproduct is purified by column chromatography with methanol:ethyl acetateto afford the title compound as yellow solid. MP: 151-154° C. ¹H-NMR (δppm, DMSO-D₆, 400 MHz): δ 12.94 (s, 1H), 8.09 (br s, 3H), 7.94 (d, J=7.9Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.42 (m, 6H), 5.22 (br t, 1H), 1.82 (d,J=6.4 Hz, 3H). Mass: 463.99 (M+1).

Illustration 8(R)-2-(1-(9H-purin-6-ylamino)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

This example is also described in Example 56 of WO 2011/055215. To asolution of (R)-2-(1-Amino-ethyl)-3-(3-fluoro-phenyl)-chromen-4-one(0.41 g, 1.52 mmoles) in tert-butanol (7 ml), N,N-diisopropylethylamine(0.53 ml, 3.04 mmoles) and 6-bromopurine (0.242 g, 1.21 mmoles) areadded and refluxed for 24 h. The reaction mixture is concentrated,diluted with water, and extracted with ethyl acetate. The organic layeris dried over sodium sulphate and concentrated under reduced pressure.The crude product is purified by column chromatography withmethanol:ethyl acetate to afford the title compound as an off-whitesolid. MP: 274-276° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 12.96 (s,1H), 8.14-8.01 (m, 4H), 8.11 (s, 1H), 7.81 (dt, J=8.5, 1.5 Hz, 1H), 7.60(d, J=8.4 Hz, 1H), 7.49 (m, 2H), 7.25-7.19 (m, 3H), 5.18 (br m, 1H),1.56 (d, J=7.0 Hz, 3H). Mass: 402.04 (M⁺+1).

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as described above. It is intended that theappended claims define the scope of the invention and that methods andstructures within the scope of these claims and their equivalents becovered thereby.

All publications, patents and patent applications cited in thisapplication are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated herein byreference.

1. A process for preparing a compound of formula (IA)

or a salt thereof, the process comprising (a) treating a compound offormula (6) with a compound of formula (A)

to give a compound of formula (7a)

(b) deprotecting the compound formed in step (a) to obtain a compound offormula (IA) and optionally converting it to its salt, wherein eachoccurrence of R is independently selected from hydrogen, hydroxy,halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenylalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heteroarylalkyl, —COOR^(x), —C(O)R^(x), —C(S)R^(x),—C(O)NR^(x)R^(y), —C(O)ONR^(x)R^(y), —NR^(x)R^(y), —NR^(x)CONR^(x)R^(y),—N(R^(x))SOR^(x), —N(R^(x))SO₂R, —(═N—N(R^(x))R^(y)), —NR^(x)C(O)OR^(y),—NR^(x)C(O)R^(y)—, —NR^(x)C(S)R^(y)—NR^(x)C(S)NR^(x)R^(y),—SONR^(x)R^(y), —SO₂NR^(x)R^(y), —OR^(x), —OR^(x)C(O)NR^(x)R^(y),—OR^(x)C(O)OR^(x), —OC(O)R^(x), —OC(O)NR^(x)R^(y),—R^(x)NR^(y)C(O)R^(Z), —R^(x)OR^(y), —R^(x)C(O)OR,—R^(x)C(O)NR^(x)R^(y), —R^(x)C(O)R^(y), —R^(x)OC(O)R^(y), —SR^(x),—SOR^(x), —SO₂R^(x), and —ONO₂, wherein each occurrence of R^(x), R^(y)and R^(z) is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted heteroaryl, substituted or unsubstitutedheteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedcycloalkenyl, substituted or unsubstituted heterocyclic ring,substituted or unsubstituted heterocyclylalkyl ring, or substituted orunsubstituted amino, or (i) any two of R^(x) and R^(y), when bound to acommon atom, are joined to form a substituted or unsubstituted,saturated or unsaturated 3-14 membered ring, which may optionallyinclude heteroatoms which may be the same or different and are selectedfrom O, NR^(z) or S, or (ii) any two of R^(x) and R^(y), when bound to acommon atom, are joined to form an oxo (═O), thio (═S) or imino(═NR^(f)) (wherein R^(f) is hydrogen or substituted or unsubstitutedalkyl); R¹ is substituted or unsubstituted C₁₋₆ alkyl; Cy¹ is amonocyclic or bicyclic group selected from substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclic group, substitutedor unsubstituted aryl and substituted or unsubstituted heteroaryl; Pg isa protecting group; and n is an integer selected from 0, 1, 2, 3 or 4.2. A process of claim 1, wherein the reaction in step (a) is performedin the presence of HATU, HBTU, TBTU, COMU, TOTU, HCTU, TCTU, TATU, TSTUor TDBTU.
 3. A process of claim 1, wherein in the deprotection reactionof step (b) is performed with aluminium chloride, boron tribromide, or acombination thereof, or by hydrogenation.
 4. A process for preparing acompound of formula (IA) of claim 1, wherein the compound of formula (6)is prepared by (a) converting a compound of formula (1)

wherein Pg is a protecting group, to a compound of formula (2)

(b) converting the compound of formula (2) to a compound of formula (3)

(c) converting the compound of formula (3) to a compound of formula (5)

wherein R, n, Cy¹ and Pg are as defined in claim 1; and (d) deprotectionof the compound of formula (5) to give a compound of formula (6)


5. A process of any one of claims 1-4, wherein the compound of formula(IA) has the formula (IA-I)

and, the process comprises the steps of (a) converting a compound offormula (1a)

to a compound of formula (2a)

wherein Pg is a protecting group; (b) converting a compound of formula(2a) to a compound of formula (3a)

(c) converting a compound of formula (3a) to a compound of formula (5a)

(d) deprotection of the compound of formula (5a) to give a compound offormula (6a)

(e) reacting the compound of formula (6a) with a compound of formula (A)

to give a compound of formula (7aa)

(f) deprotection of the compound of formula (7aa) to give the desiredcompound of formula (IA-I); and (g) optionally, converting the compoundof formula (IA-I) to a salt of the compound.
 6. A process of any one ofclaims 1-4, wherein the compound of formula (IA) has the formula (IA-II)

and comprises the steps of (a) converting a compound of formula (1b)

wherein Pg is a protecting group, to a compound of formula (2b)

(b) converting a compound of formula (2b) to a compound of formula (3b)

(c) converting the compound of formula (3b) to a compound of formula(5b)

(d) deprotection of the compound of formula (5b) to give a compound offormula (6b)

(e) reacting the compound of formula (6b) with a compound of formula (A)

to give a compound of formula (7ab)

and (f) deprotection of the compound of formula (7ab) to give thedesired compound of formula (IA-II); and (g) optionally, converting thecompound of formula (IA-II) to a salt of the compound.
 7. A process forpreparing a compound of formula (IB)

or a salt thereof, the process comprising (a) treating a compound offormula (6) with a compound of formula (B) wherein Pg is a protectinggroup

to give a compound of formula (7b)

and (b) deprotecting the compound formed in step (a) to obtain acompound of formula (IB) and optionally converting it to its salt,wherein each occurrence of R is independently selected from hydrogen,hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenylalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heteroarylalkyl, —COOR^(x), —C(O)R^(x), —C(S)R^(x),—C(O)NR^(x)R^(y), —C(O)ONR^(x)R^(y), —NR^(x)R^(y), —NR^(x)CONR^(x)R^(y),—N(R^(x))SOR^(x), —N(R^(x))SO₂R, —(═N—N(R^(x))R^(y)), —NR^(x)C(O)OR^(y),—NR^(x)C(O)R^(y)—, —NR^(x)C(S)R^(y)—NR^(x)C(S)NR^(x)R^(y),—SONR^(x)R^(y), —SO₂NR^(x)R^(y), —OR^(x), —OR^(x)C(O)NR^(x)R^(y),—OR^(x)C(O)OR^(x), —OC(O)R^(x), —OC(O)NR^(x)R^(y),—R^(x)NR^(y)C(O)R^(z), —R^(x)OR^(y), —R^(x)C(O)OR,—R^(x)C(O)NR^(x)R^(y), —R^(x)C(O)R^(y), —R^(x)OC(O)R^(y), —SR^(x),—SOR^(x), —SO₂R^(x), and —ONO₂, wherein each occurrence of R^(x), R^(y)and R^(z) is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted heteroaryl, substituted or unsubstitutedheteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedcycloalkenyl, substituted or unsubstituted heterocyclic ring,substituted or unsubstituted heterocyclylalkyl ring, or substituted orunsubstituted amino, or (i) any two of R^(x) and R^(y), when bound to acommon atom, are joined to form a substituted or unsubstituted,saturated or unsaturated 3-14 membered ring, which may optionallyinclude heteroatoms which may be the same or different and are selectedfrom O, NR^(z) or S, or (ii) any two of R^(x) and R^(y), when bound to acommon atom, are joined to form an oxo (═O), thio (═S) or imino(═NR^(f)) (wherein R^(f) is hydrogen or substituted or unsubstitutedalkyl); R¹ is substituted or unsubstituted C₁₋₆ alkyl; Cy¹ is amonocyclic or bicyclic group selected from substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclic group, substitutedor unsubstituted aryl and substituted or unsubstituted heteroaryl; Pg isa protecting group; and n is an integer selected from 0, 1, 2, 3 or 4.8. A process of claim 7, wherein the compound of formula (6) is preparedby (a) converting a compound of formula (1)

to a compound of formula (2)

wherein Pg is a protecting group; (b) converting the compound of formula(2) to a compound of formula (3)

(c) converting the compound of formula (3) to a compound of formula (5)

and (d) deprotection of the compound of formula (5) to give a compoundof formula (6)


9. A process of claim 7, wherein the reaction in step (a) is performedin the presence of HATU, HBTU, TBTU, COMU, TOTU, HCTU, TCTU, TATU, TSTU,or TDBTU.
 10. A process of claim 7, wherein the deprotection reaction ofstep (b) is performed with aluminium chloride, boron tribromide, or acombination thereof, or by hydrogenation.
 11. A process of any one ofclaims 7-10, wherein the compound of formula (IB) has the formula (IB-I)

and the process comprises the steps of (a) reacting the compound offormula (6a) with a compound of formula (B)

to give a compound of formula (7ba)

(b) deprotection of the compound of formula (7ba) to give the desiredcompound of formula (IB-I); and (c) optionally, converting the compoundof formula (IB-I) to a salt of the compound.
 12. A process of any one ofclaims 7-10, wherein the compound of formula (IB) has the formula(IB-II)

and the process comprises the steps of (a) reacting the compound offormula (6b) with a compound of formula (B)

to give a compound of formula (7bb)

(b) deprotection of the compound of formula (7bb) to give the desiredcompound of formula (IB-II); and (c) optionally, converting the compoundof formula (IB-II) to a salt of the compound.
 13. Use of the compound offormula (IA) for preparation of a PI3K inhibitor of formula (I)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof, wherein the variables R, n, Cy¹, and R¹ are defined as in claim1; Cy² is selected from a substituted or unsubstituted heterocyclicgroup, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl; L₁ is absent or selected from—(CR^(a)R^(b))_(q)—, —O—, —S(═O)_(q)—, —NR^(a)— or —C(═Y)—; eachoccurrence of R^(a) and R^(b) may be the same or different and areindependently selected from hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, —NR^(c)R^(d) (wherein R^(c)and R^(d) are independently hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, or (C₁₋₆)alkoxy) and —OR^(c)(wherein Re is substituted or unsubstituted (C₁₋₆)alkyl) or when R^(a)and R^(b) are directly bound to a common atom, they may be joined toform an oxo group (═O) or form a substituted or unsubstituted, saturatedor unsaturated 3-10 member ring (including the common atom to whichR^(a) and R^(b) are directly bound), which may optionally include one ormore heteroatoms which may be the same or different and are selectedfrom O, NR^(d) (wherein R^(d) is hydrogen or substituted orunsubstituted (C₁₋₆)alkyl) or S; Y is selected from O, S, and NR^(a);and q is 0, 1 or
 2. 14. Use of the compound of formula (IB) forpreparation of a PI3K inhibitor of formula (I)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof, wherein the variables R, n, Cy¹, and R¹ are defined as in claim1; Cy² is selected from a substituted or unsubstituted heterocyclicgroup, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl; L₁ is absent or selected from—(CR^(a)R^(b))_(q)—, —O—, —S(═O)_(q)—, —NR^(a)— or —C(═Y)—; eachoccurrence of R^(x) and R^(b) may be the same or different and areindependently selected from hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, —NR^(c)R^(d) (wherein R^(c)and R^(d) are independently hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, or (C₁₋₆)alkoxy) and —OR^(c)(wherein Re is substituted or unsubstituted (C₁₋₆)alkyl) or when R^(a)and R^(b) are directly bound to a common atom, they may be joined toform an oxo group (═O) or form a substituted or unsubstituted, saturatedor unsaturated 3-10 member ring (including the common atom to whichR^(a) and R^(b) are directly bound), which may optionally include one ormore heteroatoms which may be the same or different and are selectedfrom O, NR^(d) (wherein R^(d) is hydrogen or substituted orunsubstituted (C₁₋₆)alkyl) or S; Y is selected from O, S, and NR^(a);and q is 0, 1 or
 2. 15. A process for preparing a PI3K inhibitor offormula (I)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof, wherein the variables R, n, Cy¹, and R¹ are defined as in claim1; Cy² is selected from a substituted or unsubstituted heterocyclicgroup, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl; L₁ is absent or selected from—(CR^(a)R^(b))_(q)—, —O—, —S(═O)_(q)—, —NR^(a)— or —C(═Y)—; eachoccurrence of R^(a) and R^(b) may be the same or different and areindependently selected from hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, —NR^(c)R^(d) (wherein R^(c)and R^(d) are independently hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, or (C₁₋₆)alkoxy) and —OR^(c)(wherein Re is substituted or unsubstituted (C₁₋₆)alkyl) or when R^(a)and R^(b) are directly bound to a common atom, they may be joined toform an oxo group (═O) or form a substituted or unsubstituted, saturatedor unsaturated 3-10 member ring (including the common atom to whichR^(a) and R^(b) are directly bound), which may optionally include one ormore heteroatoms which may be the same or different and are selectedfrom O, NR^(d) (wherein R^(d) is hydrogen or substituted orunsubstituted (C₁₋₆)alkyl) or S; Y is selected from O, S, and NR^(a);and q is 0, 1 or 2, the process comprising (a) treating the compound offormula (IA) with Cy²-H to give the desired compound of formula (I) or atautomer thereof, N-oxide thereof, pharmaceutically acceptable esterthereof, prodrug thereof, or pharmaceutically acceptable salt thereof;and (b) optionally converting the compound of formula (I) to a salt ofthe compound.
 16. A process for preparing a PI3K inhibitor of formula(I)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof, wherein the variables R, n, Cy¹, and R¹ are defined as in claim1; Cy² is selected from a substituted or unsubstituted heterocyclicgroup, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl; L₁ is absent or selected from—(CR^(a)R^(b))_(q)—, —O—, —S(═O)_(q)—, —NR^(a)— or —C(═Y)—; eachoccurrence of R^(a) and R^(b) may be the same or different and areindependently selected from hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, —NR^(c)R^(d) (wherein R^(c)and R^(d) are independently hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, or (C₁₋₄)alkoxy) and —OR^(c)(wherein Re is substituted or unsubstituted (C₁₋₆)alkyl) or when R^(a)and R^(b) are directly bound to a common atom, they may be joined toform an oxo group (═O) or form a substituted or unsubstituted, saturatedor unsaturated 3-10 member ring (including the common atom to whichR^(a) and R^(b) are directly bound), which may optionally include one ormore heteroatoms which may be the same or different and are selectedfrom O, NR^(d) (wherein R^(d) is hydrogen or substituted orunsubstituted (C₁₋₆)alkyl) or S; Y is selected from O, S, and NR^(a);and q is 0, 1 or 2, the process comprising (a) treating the compound offormula (IA) with a phosphorus halide or mesyl halide in the presence ofa base to give a compound of formula (8a)

wherein X¹ is halogen or —O-Mesyl; and (b) reacting the compound offormula (8a) with Cy²-H in the presence of a base to give the desiredcompound of formula (I) or a tautomer thereof, N-oxide thereof,pharmaceutically acceptable ester thereof, prodrug thereof; and (c)optionally, converting the compound of formula (I) to a salt of thecompound.
 17. Use of the compound of formula (IA) for preparation of aPI3K inhibitor of formula (II)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof, wherein R, n, Cy¹, and R¹ are as defined in claim 1; Cy² isselected from a substituted or unsubstituted heterocyclic group,substituted or unsubstituted aryl and substituted or unsubstitutedheteroaryl; and L₁ is NH.
 18. The process of claim 17 comprising (a)treating the compound of formula (IA)

with a phosphorus halide or mesyl halide in the presence of a base togive a compound of formula (8a)

wherein X¹ is halogen or —O-Mesyl; (b) converting the compound offormula (8a) to give a compound of formula (9a)

(c) converting the compound of formula (9a) to give a compound offormula (10a)

(d) coupling the compound of formula (10a) with a compound of formulaCy²-Lg, wherein Lg is a leaving group, in the presence of a base to givethe desired compound of formula (II); and (e) optionally, converting thecompound of formula (II) to a salt of the compound.
 19. Use of thecompound of formula (IB) for preparation of a PI3K inhibitor of formula(III)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof, wherein the variables R, n, Cy¹, and R¹ are defined as in claim1; Cy² is selected from a substituted or unsubstituted heterocyclicgroup, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl; L₁ is absent or selected from—(CR^(a)R^(b))_(q)—, —O—, —S(═O)_(q)—, —NR^(a)— or —C(═Y)—; eachoccurrence of R^(a) and R^(b) may be the same or different and areindependently selected from hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, —NR^(c)R^(d) (wherein R^(c)and R^(d) are independently hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, or (C₁₋₆)alkoxy) and —OR^(c)(wherein Re is substituted or unsubstituted (C₁₋₆)alkyl) or when R^(a)and R^(b) are directly bound to a common atom, they may be joined toform an oxo group (═O) or form a substituted or unsubstituted, saturatedor unsaturated 3-10 member ring (including the common atom to whichR^(a) and R^(b) are directly bound), which may optionally include one ormore heteroatoms which may be the same or different and are selectedfrom O, NR^(d) (wherein R^(d) is hydrogen or substituted orunsubstituted (C₁₋₆)alkyl) or S; Y is selected from O, S, and NR^(a);and q is 0, 1 or
 2. 20. Use of the compound of formula (IA) forpreparation of a PI3K inhibitor of formula (III)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof, wherein the variables R, n, Cy¹, and R¹ are defined as in claim1; Cy² is selected from a substituted or unsubstituted heterocyclicgroup, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl; L₁ is absent or selected from—(CR^(a)R^(b))_(q)—, —O—, —S(═O)_(q)—, —NR^(a)— or —C(═Y)—; eachoccurrence of R^(a) and R^(b) may be the same or different and areindependently selected from hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, —NR^(c)R^(d) (wherein R^(c)and R^(d) are independently hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, or (C₁₋₆)alkoxy) and —OR^(c)(wherein Re is substituted or unsubstituted (C₁₋₆)alkyl) or when R^(a)and R^(b) are directly bound to a common atom, they may be joined toform an oxo group (═O) or form a substituted or unsubstituted, saturatedor unsaturated 3-10 member ring (including the common atom to whichR^(a) and R^(b) are directly bound), which may optionally include one ormore heteroatoms which may be the same or different and are selectedfrom O, NR^(d) (wherein R^(d) is hydrogen or substituted orunsubstituted (C₁₋₆)alkyl) or S; Y is selected from O, S, and NR^(a);and q is 0, 1 or
 2. 21. A process for preparing a PI3K inhibitor offormula (III)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof, wherein the variables R, n, Cy¹, and R¹ are defined as in claim1; Cy² is selected from a substituted or unsubstituted heterocyclicgroup, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl; L₁ is absent or selected from—(CR^(a)R^(b))_(q)—, —O—, —S(═O)_(q)—, —NR^(a)— or —C(═Y)—; eachoccurrence of R^(a) and R^(b) may be the same or different and areindependently selected from hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, —NR^(c)R^(d) (wherein R^(c)and R^(d) are independently hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, or (C₁₋₆)alkoxy) and —OR^(c)(wherein Re is substituted or unsubstituted (C₁₋₆)alkyl) or when R^(a)and R^(b) are directly bound to a common atom, they may be joined toform an oxo group (═O) or form a substituted or unsubstituted, saturatedor unsaturated 3-10 member ring (including the common atom to whichR^(a) and R^(b) are directly bound), which may optionally include one ormore heteroatoms which may be the same or different and are selectedfrom O, NR^(d) (wherein R^(d) is hydrogen or substituted orunsubstituted (C₁₋₆)alkyl) or S; Y is selected from O, S, and NR^(a);and q is 0, 1 or 2, the process comprising (a) treating the compound offormula (IB) with Cy²-H to give the desired compound of formula (III) ora tautomer thereof, N-oxide thereof, pharmaceutically acceptable esterthereof, prodrug thereof, or pharmaceutically acceptable salt thereof;and (b) optionally converting the compound of formula (III) to a salt ofthe compound.
 22. A process for preparing a PI3K inhibitor of formula(III)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof, wherein the variables R, n, Cy¹, and R¹ are defined as in claim1; Cy² is selected from a substituted or unsubstituted heterocyclicgroup, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl; L₁ is absent or selected from—(CR^(a)R^(b))_(q)—, —O—, —S(═O)_(q)—, —NR^(a)— or —C(═Y)—; eachoccurrence of R^(a) and R^(b) may be the same or different and areindependently selected from hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, —NR^(c)R^(d) (wherein R^(c)and R^(d) are independently hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, or (C₁₋₆)alkoxy) and —OR^(c)(wherein Re is substituted or unsubstituted (C₁₋₆)alkyl) or when R^(a)and R^(b) are directly bound to a common atom, they may be joined toform an oxo group (═O) or form a substituted or unsubstituted, saturatedor unsaturated 3-10 member ring (including the common atom to whichR^(a) and R^(b) are directly bound), which may optionally include one ormore heteroatoms which may be the same or different and are selectedfrom O, NR^(d) (wherein R^(d) is hydrogen or substituted orunsubstituted (C₁₋₆)alkyl) or S; Y is selected from O, S, and NR^(a);and q is 0, 1 or 2, the process comprising (f) treating the compound offormula (IB) with a phosphorus halide or mesyl halide in the presence ofa base to give a compound of formula (8b)

wherein X¹ is halogen or —O-Mesyl; and (g) reacting the compound offormula (8b) with Cy²-H in the presence of a base to give the desiredcompound of formula (III) or a tautomer thereof, N-oxide thereof,pharmaceutically acceptable ester thereof, prodrug thereof; and (h)optionally, converting the compound of formula (III) to a salt of thecompound.
 23. Use of the compound of formula (IB) for preparation of aPI3K inhibitor of formula (IV)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof, wherein R, n, Cy¹, and R¹ are as defined in claim 1; Cy² isselected from a substituted or unsubstituted heterocyclic group,substituted or unsubstituted aryl and substituted or unsubstitutedheteroaryl; and L₁ is NH.
 24. A process for preparing a PI3K inhibitorof formula (IV) of claim 23 comprising (i) treating the compound offormula (IB)

with a phosphorus halide or mesyl halide in the presence of a base togive a compound of formula (8b)

wherein X¹ is halogen or —O-Mesyl; (j) converting the compound offormula (8b) to give a compound of formula (9b)

(k) converting the compound of formula (9b) to give a compound offormula (10b)

(l) coupling the compound of formula (10b) with a compound of formulaCy²-Lg, wherein Lg is a leaving group, in the presence of a base to givethe desired compound of formula (IV); and (m) optionally, converting thecompound of formula (IV) to a salt of the compound.
 25. A process forinverting a compound of formula (IA) to yield a compound of formula (IB)wherein the process comprises the step of (a) reacting the compound offormula (IA) with R′—COOH (wherein R′ is selected from substituted orunsubstituted alkyl or substituted or unsubstituted aryl) to provide acompound of formula IA-2

and (b) treating the compound of formula (IA-2) to yield a compound offormula (IB)
 26. A process for inverting a compound of formula (IB) toyield a compound of formula (IA) wherein the process comprises the stepof (a) reacting the compound of formula (IB) with R′—COOH (wherein R′ isselected from substituted or unsubstituted alkyl or aryl) to provide acompound of formula IB-2

(b) treating the compound of formula (IB-2) to yield a compound offormula (IA)
 27. A process of claim 25 or 26 wherein R¹ is 4-Chlorophenyl
 28. A compound of formula (IA) or (IB)

or a salt thereof, wherein each occurrence of R is independentlyselected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted heteroaryl,substituted or unsubstituted heteroarylalkyl, —COOR^(x), —C(O)R^(x),—C(S)R^(x), —C(O)NR^(x)R^(y), —C(O)ONR^(x)R^(y), —NR^(x)R^(y),—NR^(x)CONR^(x)R^(y), —N(R^(x))SOR^(x), —N(R^(x))SO₂R,—(═N—N(R^(x))R^(y)), —NR^(x)C(O)OR^(y), —NR^(x)C(O)R^(y)—,—NR^(x)C(S)R^(y)—NR^(x)C(S)NR^(x)R^(y), —SONR^(x)R^(y), —SO₂NR^(x)R^(y),—OR^(x), —OR^(x)C(O)NR^(x)R^(y), —OR^(x)C(O)OR^(x), —OC(O)R^(x),—OC(O)NR^(x)R^(y), —R^(x)NR^(y)C(O)R^(Z), —R^(x)OR^(y), —R^(x)C(O)OR,—R^(x)C(O)NR^(x)R^(y), —R^(x)C(O)R^(y), —R^(x)OC(O)R^(y), —SR^(x),—SOR^(x), —SO₂R^(x), and —ONO₂, wherein each occurrence of R^(x), R^(y)and R^(z) is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted heteroaryl, substituted or unsubstitutedheteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedcycloalkenyl, substituted or unsubstituted heterocyclic ring,substituted or unsubstituted heterocyclylalkyl ring, or substituted orunsubstituted amino, or (i) any two of R^(x) and R^(y), when bound to acommon atom, are joined to form a substituted or unsubstituted,saturated or unsaturated 3-14 membered ring, which may optionallyinclude heteroatoms which may be the same or different and are selectedfrom O, NR^(z) or S, or (ii) any two of R^(x) and R^(y), when bound to acommon atom, are joined to form an oxo (═O), thio (═S) or imino(═NR^(f)) (wherein R^(f) is hydrogen or substituted or unsubstitutedalkyl); R¹ is substituted or unsubstituted C₁₋₆ alkyl; Cy¹ is a groupselected from substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclic group, substituted or unsubstituted aryl andsubstituted or unsubstituted heteroaryl; and n is an integer selectedfrom 0, 1, 2, 3 or 4, wherein the compound is not selected from

or a salt thereof.
 29. A compound of claim 28, wherein R is alkyl orhalogen.
 30. A compound of claim 28 or 29, wherein R is chloro, fluoroor methyl.
 31. A compound of any one of claims 28-30, wherein Cy¹ is amonocyclic group selected from substituted or unsubstituted aryl.
 32. Acompound of claim 31, wherein Cy¹ is selected from.


33. A compound of any one of claims 28-32, wherein R¹ is methyl orethyl.
 34. A compound of claim 28-33, wherein n is
 1. 35. A compound ofany one of claims 28-24, wherein the compound has an enantiomeric excessof at least 75%, 90%, 95%, 97%, or 98%.
 36. A compound selected from(R)-6-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one;(R)-2-(1-hydroxyethyl)-5-methyl-3-phenyl-4H-chromen-4-one;(R)-6-fluoro-2-(1-hydroxyethyl)-3-phenyl-4H-chromen-4-one;(R)-2-(1-hydroxyethyl)-3-phenyl-4H-chromen-4-one;(R)-3-(3-fluorophenyl)-2-(1-hydroxypropyl)-4H-chromen-4-one;(R)-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one;(S)-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one; and saltsthereof.
 37. A composition comprising (a) a compound of formula (IA) or(IB) or a salt thereof, (b) a PI3K inhibitor of formula (I)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof, wherein the variables R, n, Cy¹, and R¹ are defined as in claim1; Cy² is selected from a substituted or unsubstituted heterocyclicgroup, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl; L₁ is absent or selected from—(CR^(a)R^(b))_(q)—, —O—, —S(═O)_(q)—, —NR^(a)— or —C(═Y)—; eachoccurrence of R^(a) and R^(b) may be the same or different and areindependently selected from hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, —NR^(c)R^(d) (wherein R^(c)and R^(d) are independently hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, or (C₁₋₆)alkoxy) and —OR^(c)(wherein Re is substituted or unsubstituted (C₁₋₆)alkyl) or when R^(a)and R^(b) are directly bound to a common atom, they may be joined toform an oxo group (═O) or form a substituted or unsubstituted, saturatedor unsaturated 3-10 member ring (including the common atom to whichR^(a) and R^(b) are directly bound), which may optionally include one ormore heteroatoms which may be the same or different and are selectedfrom O, NR^(d) (wherein R^(d) is hydrogen or substituted orunsubstituted (C₁₋₆)alkyl) or S; Y is selected from O, S, and NR^(a);and q is 0, 1 or 2, wherein the compound of formula (IA) or (IB) ispresent in an amount up to 0.5% by weight, based upon the total ofcomponents (a) and (b).
 38. A composition comprising (a) a compound offormula (IA) or (IB) or a salt thereof, (b) a PI3K inhibitor of formula(III)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof, wherein the variables R, n, Cy¹, and R¹ are defined as in claim1; Cy² is selected from a substituted or unsubstituted heterocyclicgroup, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl; L₁ is absent or selected from—(CR^(a)R^(b))_(q)—, —O—, —S(═O)_(q)—, —NR^(a)— or —C(═Y)—; eachoccurrence of R^(a) and R^(b) may be the same or different and areindependently selected from hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, —NR^(c)R^(d) (wherein R^(c)and R^(d) are independently hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, or (C₁₋₆)alkoxy) and —OR^(c)(wherein Re is substituted or unsubstituted (C₁₋₆)alkyl) or when R^(a)and R^(b) are directly bound to a common atom, they may be joined toform an oxo group (═O) or form a substituted or unsubstituted, saturatedor unsaturated 3-10 member ring (including the common atom to whichR^(a) and R^(b) are directly bound), which may optionally include one ormore heteroatoms which may be the same or different and are selectedfrom O, NR^(d) (wherein R^(d) is hydrogen or substituted orunsubstituted (C₁₋₆)alkyl) or S; Y is selected from O, S, and NR^(a);and q is 0, 1 or 2, wherein the compound of formula (IA) or (IB) ispresent in an amount up to 0.5% by weight, based upon the total ofcomponents (a) and (b).
 39. The composition of claim 37 or 38, whereinthe compound of formula (IA) or (IB) is present in an amount up to 0.2%by weight, based upon the total of components (a) and (b).